Novel phloretin-based combinations targeting glucose metabolism in hepatocellular carcinoma through GLUT2/PEPCK axis of action: in silico molecular modelling and in vivo studies.

Autor: Elmetwalli A; Department of Clinical Trial Research Unit and Drug Discovery, Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt. dr.prof2011@gmail.com.; Microbiology Division, Higher Technological Institute of Applied Health Sciences, Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt. dr.prof2011@gmail.com., Kamosh NH; Laboratory Specialist, Alexandria, Egypt., El Safty R; Laboratory Specialist, Alexandria, Egypt., Youssef AI; Department of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt., Salama MM; Department of Histochemistry and Cell Biology, Medical Research Institute, Alexandria University, Alexandria, Egypt., Abd El-Razek KM; Experimental Animal Unit, Medical Research Institute, Alexandria University, Alexandria, Egypt., El-Sewedy T; Department of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Jazyk: angličtina
Zdroj: Medical oncology (Northwood, London, England) [Med Oncol] 2023 Dec 11; Vol. 41 (1), pp. 12. Date of Electronic Publication: 2023 Dec 11.
DOI: 10.1007/s12032-023-02236-x
Abstrakt: Hepatocellular carcinoma (HCC) is commonly associated with disturbances in glucose metabolism and enhanced glycolysis. However, a controversial role for gluconeogenesis was reported to be tumor-promoting and tumor-suppressive. We investigated novel anti-HCC treatments through either the simultaneous inhibition of glycolysis and gluconeogenesis by "phloretin" and "sodium meta-arsenite", respectively (Combination 1); or the concurrent inhibition of glycolysis and induction of gluconeogenesis by phloretin and dexamethasone, respectively, (combination 2). A total of 110 Swiss albino mice were divided into eleven groups, HCC was induced by N, N-dimethyl-4-aminoazobenzene. We have measured the expression of the glucose transporter 2 (GLUT2), Phosphoenolpyruvate carboxykinases (PEPCK), Caspase-3, Beclin 1, Cyclin D1, and cytokeratin 18 genes; blood glucose and ATP levels; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Furthermore, in silico molecular docking was performed to investigate the potential drug-receptor interactions. Histologically, the phloretin-based combinations resulted in a significant regression of malignant tissue compared to various treatments. GLUT2 and PEPCK mRNA analysis indicated successful off/on modulation of glycolysis and gluconeogenesis. Docking confirmed the potent binding between phloretin, sodium meta-arsenite, and dexamethasone with GLUT2, PEPCK, and Retinoid X Receptor Alpha, respectively. Molecularly, Combination 2 resulted in the highest reduction in cyclin D1, cytokeratin 18, and Beclin 1 expression contemporaneously with the upregulation in Caspase-3 levels. Biochemically, both combinations caused a significant reduction in ATP levels, ALT, and AST activity compared to the other groups. In conclusion, we propose two novel phloretin-based combinations that can be used in treating HCC through the regulation of glucose metabolism and ATP production.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
Externí odkaz: